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Figure 1.—Sex and age risk factors for cardiac arrhythmias attributed to erythromycin. A, All cases of cardiac arrhythmias related to any erythromycin product reported to the Food and Drug Administration between 1970 and 1996 (n=311). B, Odds ratio and 95% confidence interval for female sex as a risk factor for the development of erythromycin-associated arrhythmias, at different patient age. Values were adjusted for sex differences in drug exposure, which was estimated from a large prescription survey. C, Life-threatening arrhythmias (torsades de pointes, ventricular tachycardia, ventricular fibrillation, and cardiac arrests) directly related to administration of intravenous erythromycin lactobionate from 1986 until 1996 (n=49). The P value for female reproductive age is .05.
Image description not available.
Figure 2.—Sex difference in the effects of increasing concentrations of erythromycin lactobionate in isolated rabbit hearts perfused by the Langendorff technique (n=10). Relative changes in the QT interval are expressed as mean (SEM). The QT interval lengthens significantly more in female compared with male rabbit hearts. At 1 µmol/L, P = .05; at 10 µmol/L, P = .009; and at 100 µmol/L, P = .08.
1.
Ponsonnaille J, Citron B, Richard A.  et al.  Etude electrophysiologique des effets pro-arythmogenes de l'erythromycine.  Arch Mal Coeur Vaiss.1988;81:1001-1008.
2.
Vogt AW, Zollo RA. Long QT syndrome associated with oral erythromycin used in preoperative bowel preparation.  Anesth Analg.1997;85:1011-1013.
3.
Oberg KC, Bauman JL. QT interval prolongation and torsades de pointes due to erythromycin lactobionate.  Pharmacotherapy.1995;15:687-692.
4.
Freedman RA, Anderson KP, Green LS, Mason JW. Effect of erythromycin on ventricular arrhythmias and ventricular repolarization in idiopathic long QT syndrome.  Am J Cardiol.1987;59:168-169.
5.
McComb JM, Campbell NPS, Cleland J. Recurrent ventricular tachycardia associated with QT prolongation after mitral valve replacement and its association with intravenous administration of erythromycin.  Am J Cardiol.1984;54:922-923.
6.
Antzelevitch C, Zhuo-Quian S, Zi-Qing Z, Gan-Xin Y. Cellular and ionic mechanisms underlying erythromycin-induced long QT intervals and torsade de pointes.  J Am Coll Cardiol.1996;28:1836-1848.
7.
Bazett HC. An analysis of the time relationship of electrocardiograms.  Heart.1920;7:353-370.
8.
Rautaharju P, Zhou S, Wong S.  et al.  Sex differences in the evolution of the electrocardiographic QT interval with age.  Can J Cardiol.1992;8:690-695.
9.
Drici M, Burklow T, Haridasse V, Glazer R, Woosley R. Sex hormones prolong the QT interval and down regulate potassium channel expression in the rabbit heart.  Circulation.1996;94:1471-1474.
10.
Makkar R, Fromm B, Steihman R, Meissner M, Lehmann M. Female gender as a risk factor for torsades de pointes associated with cardiovascular drugs.  JAMA.1993;270:2590-2597.
11.
Lehmann MH, Hardy S, Archibald D, Quart B, MacNeil D. Sex difference in risk of torsade de pointes with d,1-sotalol.  Circulation.1996;94:2535-2541.
12.
Austin KL, Mather LE, Philpot CR, McDonald PJ. Intersubject and dose-related variability after intravenous administration of erythromycin.  Br J Clin Pharmacol.1980;10:273-279.
13.
Lehmann MH, Timothy KW, Frankovich D.  et al.  Age-gender influence on the rate-corrected QT interval and the QT-heart rate relation in families with genotypically characterized long QT syndrome.  J Am Coll Cardiol.1997;29:93-99.
14.
Locati EH, Zareba W, Moss AJ.  et al.  Age- and sex-related differences in clinical manifestations in patients with congenital long-QT syndrome: findings from the International LQTS Registry.  Circulation.1998;97:2237-2244.
15.
Burke JH, Ehlert FA, Kruse JT, Parker MA, Goldberger JJ, Kadish AH. Gender-specific differences in the QT interval and the effect of autonomic tone and menstrual cycle in healthy adults.  Am J Cardiol.1997;79:178-181.
Brief Report
November 25, 1998

Cardiac Actions of ErythromycinInfluence of Female Sex

Author Affiliations

From Georgetown University Medical Center, Washington, DC. Dr Drici is now with the University of Nice-Sophia Antipolis, Nice, France.

JAMA. 1998;280(20):1774-1776. doi:10.1001/jama.280.20.1774
Context.—

Context.— Erythromycin is a widely used antibiotic that infrequently causes QT-prolongation and torsades de pointes cardiac arrhythmias. For antiarrhythmic drugs, women are at a higher risk for these cardiac arrhythmias, but few other classes of drugs have been studied.

Objectives.— To determine whether female sex is a risk factor for cardiac arrhythmias associated with erythromycin, and if this can be correlated with in vitro measurements of the QT-response to erythromycin in male and female rabbit hearts.

Design.— Food and Drug Administration (FDA) MEDWATCH database analysis and in vitro experiment.

Main Outcome Measures.— Cardiac arrhythmia reports associated with erythromycin from 1970 until 1996 classified by patient sex and age, and effect of female sex on erythromycin-induced QT-prolongation in isolated perfused rabbit hearts.

Results.— We observed a sex difference in cardiac arrhythmias associated with administration of erythromycin. A total of 346 cases were found in the FDA database: 201 females (58%), 110 males (32%), and 35 unspecified (10%). Forty-nine were life-threatening ventricular arrhythmias and deaths directly related to intravenous erythromycin lactobionate: 33 women (67%) and 16 men (33%) (P = .03). During the same period, no sex imbalance was present in the prescription pattern for intravenous erythromycin lacobionate (men 47%, women 49%, unspecified 4%). Perfusion with erythromycin caused significantly greater QT-prolongation in female rabbit hearts (mean [SD], 11.8% [2.3%]) than in male hearts (6.9% [2.1%]; P = .03).

Conclusions.— As has been shown in reports of antiarrhythmic drugs, we found a female predominance in the FDA reports of erythromycin-associated cardiac arrhythmias. Based on in vitro experiments, a sex difference in cardiac repolarization response to erythromycin is a potential contributing factor.

ERYTHROMYCIN is a widely used macrolide antibiotic for which lengthening of the rate-corrected QT interval (QTc) on the electrocardiogram (ECG) has been reported.1,2 A prolonged QTc interval on the ECG is a feature associated with drug-induced torsades de pointes (TdP), an arrhythmia reported in patients treated with erythromycin.36

Men between the ages of 15 and 60 years have a shorter QTc interval than women of the same age.7,8 Our previously reported experiments in ovariectomized rabbits have suggested that an action of sex hormones on myocardial tissue is responsible for this difference.9 Likewise, this is supported by the strong sex difference in the clinical occurrence of TdP with antiarrhythmic drugs. A preponderance of the cases (70%) occur in women compared with the predicted incidence of 40%.10,11

To evaluate the potential influence of sex and age on the cardiac adverse effects of erythromycin, we searched the Food and Drug Administration's (FDA's) MEDWATCH Spontaneous Reporting System (SRS) for such events. The overall pattern of erythromycin usage was estimated from the National Disease and Therapeutic Index (NDTI, IMS Health Inc, Plymouth Meeting, Pa). We then used an in vitro model to examine a potential sex difference in the effect of erythromycin on the QTc interval of isolated perfused rabbit hearts.

METHODS
FDA MEDWATCH Database

The FDA SRS database consists of voluntary reports of adverse events associated with drugs marketed in the United States that are submitted primarily by health care professionals. A search of the FDA SRS database was conducted to identify adverse drug reaction reports associated with erythromycin products between 1970 and 1996 under the Freedom of Information Act. The search was limited to cardiovascular arrhythmias, such as ventricular fibrillation, TdP, heart arrest, tachycardia, bradycardia, atrioventricular blocks, extrasystoles, QT interval prolongation, ECG abnormalities, and combinations of these terms. The reports were classified according to the sex and age of the patient.

To estimate the sex and age distribution of erythromycin use in the United States, drug prescription audits included in the NDTI were analyzed for the years 1991 to 1996. The NDTI is a survey designed to provide statistical information about the patterns and treatment of disease encountered in office-based practice in the United States. Prescriptions for erythromycin lactobionate filled at Georgetown University Medical Center, Washington, DC, were analyzed similarly.

Langendorff Isolated Perfused Heart Experiments

Experiments were conducted in accordance with the guidelines of the Georgetown University Animal Care and Use Committee. Five male and 5 female albino New Zealand rabbits were studied. The Langendorff method for isolated heart perfusion and measurement of QT intervals was used as described previously.9 Briefly, the hearts were excised, mounted in a modified Langendorff perfusion apparatus, paced at a constant cycle length of 400 milliseconds, and perfused with modified Tyrode solution at 37°C. Increasing concentrations of erythromycin lactobionate (Abbott Laboratories Inc, Abbott Park, Ill) at 1, 10, and 100 µmol/L were added for successive periods of 40 minutes to study the QTc response at concentrations similar to the range reached in plasma during clinical therapy (10-50 µmol/L).1,12 Three standard ECG leads were recorded and the QTc interval measured by 2 blinded investigators (M.D.D. and W.-X.W.), as previously described.9 After equilibration of the preparation for baseline measurements, erythromycin was added to the perfusion for 40 minutes. At baseline and again at the end of the erythromycin perfusion of 100 µmol/L, the pacing cycle length was switched abruptly to 1000 milliseconds for 5 minutes, then back to 400 milliseconds, to determine the magnitude of the effect of erythromycin at different pacing rates (rate dependence).

Data Analysis and Statistics

Sex differences of adverse drug reaction reports were tested by the χ2 statistic ([Observed Values−Expected Values]2/Expected Values), with P<.05 considered significant. Expected values and odds ratios were calculated on the basis of observed adverse events in each sex and the sex distribution from the NDTI database. Confidence intervals for the odds ratios were based on central limit theorem estimates. The effect of erythromycin on QT intervals was tested by analysis of variance, with Bonferroni-Dunn correction.

RESULTS
Adverse Reaction Reports and Erythromycin Prescriptions

From 1970 through 1996, 346 incidents of cardiac arrhythmias involving erythromycin products were reported via the FDA SRS. Sex was not reported in 35 cases. Overall, significantly more cases of arrhythmias occurred in women compared with men (201 vs 110, P=2.5×10−7). This was especially apparent between the ages of 10 and 59 years (Figure 1, A).

A potential cause of the higher incidence of arrhythmias in women could have been a greater number of prescriptions of erythromycin for women. We therefore analyzed the age and sex distribution in the NDTI. From 1991 to 1996, a total of 78 million prescriptions for erythromycin products were written: 56% for women, 41% for men, and 3% for patients whose sex was not specified. We then used the age-specific sex difference in erythromycin prescriptions to estimate any underlying sex difference in erythromycin exposure. Figure 1, B shows the odds ratios for female sex as a risk factor for erythromycin-related arrhythmias, calculated for each age decade. The overall increased risk for women remained statistically significant, with female sex a risk factor, especially during the reproductive years.

Because of the nature of the FDA SRS database of adverse drug events, duplicate entries can occur, and often the causal relationship between drug exposure and adverse reaction is poorly defined. To validate the results of our initial search strategy, we reviewed all reports related to the intravenous administration of erythromycin and selected only life-threatening arrhythmias (ventricular tachycardia, TdP, ventricular fibrillation, and cardiac arrest) directly associated with the infusion of erythromycin lactobionate. Forty-nine cases were documented. Again, predominantly female patients were affected: 33 female cases (67%) and 16 male cases (33%) were described (P=.03). Torsades de pointes or ventricular tachycardia in the presence of a long QTc interval was specifically reported in 36 cases (24 females and 12 males, P=.05). The sex difference was most apparent between the ages of 15 and 50 years (Figure 1, C). The prescription pattern for the intravenous formulation erythromycin lactobionate, which accounted for one third of all reported arrhythmias, was more balanced between male and female patients than oral erythromycin. One million erythromycin lactobionate prescriptions were reported, 47% to male patients and 49% to female patients. Sex was unspecified in 4% of the cases. Similarly, at Georgetown University Medical Center during the same period erythromycin lactobionate was given to 846 patients, 49% male and 51% female.

Influence of Sex on Erythromycin's Electrophysiologic Actions

We then studied the effect of erythromycin in isolated hearts from female and male rabbits. At baseline, females had a QT interval (SD) of 240 (2) milliseconds vs 232 (4) milliseconds in male rabbit hearts (P=.16). Perfusion of 1 and 10 µmol/L of erythromycin lactobionate increased the QT interval to 244 (3) milliseconds and 250 (3) milliseconds in females, and did not change the QT interval in males (228 [4] milliseconds and 229 [8] milliseconds; P = .01 between sexes). The perfusion with 100 µmol/L of erythromycin lactobionate increased the QT interval in both sexes with a resulting QT duration at steady state of 266 (6) milliseconds in females vs 243 (4) milliseconds in males (P = .01). This represented a prolongation of 11.8% (2.3%) in female hearts compared with 6.9% (2.1%) in male hearts (Figure 2). The overall drug-effect relationship was significantly different in males and females (P = .03), with males requiring more than 10 times the concentration of erythromycin as females to produce the same QT interval prolongation.

The sex difference was even more prominent at the slower pacing rate studied. Under baseline conditions, a switch to a slower pacing rate prolonged the QT interval similarly in both sexes: 18.8% (1.8%) in females vs 19.3% (1.2%) in males (P=.82). With 100 µmol/L of erythromycin lactobionate, the same change from rapid to slow pacing produced more pronounced QT interval prolongation in females (26.1% [2.3%]) than in males (22.8% [1.6%]; P = .003). Perfusion with erythromycin caused significantly greater QT-prolongation in female rabbit hearts than in male rabbit hearts (P = .03).

COMMENT

This study demonstrates a sex difference in the reported adverse cardiac effects associated with erythromycin, with a preponderance in women (about two thirds), even when corrected for differences in the number of prescriptions written for each sex. This was particularly true for arrhythmias associated with the intravenous formulation of erythromycin, erythromycin lactobionate. Our findings also demonstrate a sex difference in erythromycin's ability to induce QT interval prolongation in isolated perfused rabbit hearts. We showed that erythromycin displays a sex-related reverse rate dependence, ie, a greater QT interval lengthening at slow heart rate (60/min) in females. Those 2 results together with our prior demonstration of a male sex hormone–induced blunting of cardiac response to quinidine's effect on repolarization9 might contribute to the strong sex difference that we observed in the retrospective reports of cardiovascular adverse effects induced by erythromycin.

There were considerably more cardiac arrhythmias reported in women between the ages of 15 and 50 years than in men. This is the same age when the sex difference in QTc interval is greatest between men and women.8 Similar observations have been made in patients with familial long QT syndrome. Men exhibit shorter QTc intervals than both women and children,13 and after puberty women are at a higher risk for arrhythmic events than men.14

The greater risk of women to develop TdP during therapy with potassium channel blockers has been recognized with antiarrhythmic drugs for several years.10,15 Because of the differences in body size and the fact that men and women are often given the same dose, higher serum concentrations could be responsible for the increased risk of TdP in women. However, this is not necessarily the case for erythromycin, because the rate of erythromycin metabolism is higher in women.12 Our current results in isolated male and female rabbit hearts indicate that the 2 sexes have a quantitative difference in response to the same drug concentration.

The data from the FDA SRS database must be interpreted with caution because of the inherent limitations of a spontaneous voluntary reporting system. Possibly only as few as 1 in 10 or 1 in 100 serious adverse events are actually reported to the FDA. However, we are not aware of any factors that would introduce a sex bias in voluntary reporting. Based on our prescription survey data, we conclude that at least for intravenous erythromycin the prescription pattern had no sex bias.

In summary, we have found that the clinical case reports of cardiac arrhythmias associated with erythromycin display a significant sex difference with a predominance in women. Experimentally, normal male and female rabbit hearts have a different profile of QT interval lengthening during perfusion with erythromycin lactobionate, with a blunted response to erythromycin in male hearts. Therefore, we hypothesize that an increased sensitivity to erythromycin in women could facilitate, especially at slow heart rates, the induction of TdP ventricular arrhythmias.

References
1.
Ponsonnaille J, Citron B, Richard A.  et al.  Etude electrophysiologique des effets pro-arythmogenes de l'erythromycine.  Arch Mal Coeur Vaiss.1988;81:1001-1008.
2.
Vogt AW, Zollo RA. Long QT syndrome associated with oral erythromycin used in preoperative bowel preparation.  Anesth Analg.1997;85:1011-1013.
3.
Oberg KC, Bauman JL. QT interval prolongation and torsades de pointes due to erythromycin lactobionate.  Pharmacotherapy.1995;15:687-692.
4.
Freedman RA, Anderson KP, Green LS, Mason JW. Effect of erythromycin on ventricular arrhythmias and ventricular repolarization in idiopathic long QT syndrome.  Am J Cardiol.1987;59:168-169.
5.
McComb JM, Campbell NPS, Cleland J. Recurrent ventricular tachycardia associated with QT prolongation after mitral valve replacement and its association with intravenous administration of erythromycin.  Am J Cardiol.1984;54:922-923.
6.
Antzelevitch C, Zhuo-Quian S, Zi-Qing Z, Gan-Xin Y. Cellular and ionic mechanisms underlying erythromycin-induced long QT intervals and torsade de pointes.  J Am Coll Cardiol.1996;28:1836-1848.
7.
Bazett HC. An analysis of the time relationship of electrocardiograms.  Heart.1920;7:353-370.
8.
Rautaharju P, Zhou S, Wong S.  et al.  Sex differences in the evolution of the electrocardiographic QT interval with age.  Can J Cardiol.1992;8:690-695.
9.
Drici M, Burklow T, Haridasse V, Glazer R, Woosley R. Sex hormones prolong the QT interval and down regulate potassium channel expression in the rabbit heart.  Circulation.1996;94:1471-1474.
10.
Makkar R, Fromm B, Steihman R, Meissner M, Lehmann M. Female gender as a risk factor for torsades de pointes associated with cardiovascular drugs.  JAMA.1993;270:2590-2597.
11.
Lehmann MH, Hardy S, Archibald D, Quart B, MacNeil D. Sex difference in risk of torsade de pointes with d,1-sotalol.  Circulation.1996;94:2535-2541.
12.
Austin KL, Mather LE, Philpot CR, McDonald PJ. Intersubject and dose-related variability after intravenous administration of erythromycin.  Br J Clin Pharmacol.1980;10:273-279.
13.
Lehmann MH, Timothy KW, Frankovich D.  et al.  Age-gender influence on the rate-corrected QT interval and the QT-heart rate relation in families with genotypically characterized long QT syndrome.  J Am Coll Cardiol.1997;29:93-99.
14.
Locati EH, Zareba W, Moss AJ.  et al.  Age- and sex-related differences in clinical manifestations in patients with congenital long-QT syndrome: findings from the International LQTS Registry.  Circulation.1998;97:2237-2244.
15.
Burke JH, Ehlert FA, Kruse JT, Parker MA, Goldberger JJ, Kadish AH. Gender-specific differences in the QT interval and the effect of autonomic tone and menstrual cycle in healthy adults.  Am J Cardiol.1997;79:178-181.
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